Substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds

ABSTRACT

The invention relates to substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds, to a method for the production thereof, to medicaments containing said compounds and to their use in the production of medicaments.

[0001] The present invention relates to substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds, a processfor the production thereof, pharmaceutical preparations containing thesecompounds and the use of these compounds for the production ofpharmaceutical preparations.

[0002] Pain is one of the basic clinical symptoms. There is a worldwideneed for effective pain treatments. The urgency of the requirement foreffective therapeutic methods for providing tailored and targetedtreatment of chronic and non-chronic pain, this being taken to mean paintreatment which is effective and satisfactory from the patient'sstandpoint, is evident from the large number of scientific papersrelating to applied analgesia and to basic nociception research whichhave appeared in recent times.

[0003] Conventional opioids, such as for example morphine, are effectivein the treatment of severe to very severe pain. However, they produceaccompanying symptoms which include respiratory depression, vomiting,sedation, constipation and development of tolerance. Research is beingcarried out worldwide into other pain-relieving agents.

[0004] The object of the present invention was accordingly to providenew compounds which are particularly suitable as pharmaceutical activeingredients in pharmaceutical preparations.

[0005] These active ingredients are intended in particular to combatpain. Moreover, the active ingredients are also intended to be suitablefor the treatment of depression, hypotension, hypertension, seniledementia, Alzheimer's disease, general cognitive dysfunction, tinnitus,hardness of hearing, epilepsy, obesity, cachexia, urinary incontinenceor anxiolysis or diuresis.

[0006] According to the invention, this object is achieved by theprovision of substituted 1-aryl-but-3-enylamine and1-aryl-but-2-enylamine compounds of formula I below, which exhibit apronounced analgesic effect and which are also suitable in particularfor the treatment of depression, hypotension, hypertension, seniledementia, Alzheimer's disease, general cognitive dysfunction, tinnitus,hardness of hearing, epilepsy, obesity, cachexia, urinary incontinenceor anxiolysis or diuresis.

[0007] The present invention accordingly provides substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds of thegeneral formula I,

[0008] in which

[0009] R¹ and R², identical or different, denote a C₁₋₆ alkyl residue ortogether form a (CH₂)₂₋₆ ring, which may also be substituted orbenzo-fused with at least one optionally at least mono-substituted arylor heteroaryl residue,

[0010] preferably together form a (CH₂)₂₋₆ ring, which may also besubstituted or benzo-fused with at least one optionally at leastmono-substituted aryl or heteroaryl residue, particularly preferablytogether form a cyclohexyl ring, which may also be substituted with anoptionally at least mono-substituted phenyl residue,

[0011] R³ denotes a C₃₋₆ alkyl, a C₃₋₇ cycloalkyl, an optionally atleast mono-substituted aryl or heteroaryl residue or an optionally atleast mono-substituted aryl or heteroaryl residue attached via a C₁₋₃alkylene group, preferably an optionally at least mono-substituted arylresidue or an optionally at least mono-substituted aryl residue attachedvia a C₁₋₃ alkylene group, particularly preferably an optionally atleast mono-substituted phenyl, benzyl or phenethyl residue,

[0012] R⁴ and R⁵, identical or different, denote a C₁₋₆ alkyl, a C₃₋₇cycloalkyl, a phenyl, a benzyl or a phenethyl residue or R⁴ and R⁵together form a (CH₂)₃₋₆ or —CH₂—CH₂—O—CH₂—CH₂ ring, preferably,identical or different, denote a C₁₋₆ alkyl residue or together form a—(CH₂)₅ or —CH₂—CH₂—O—CH₂—CH₂ ring, particularly preferably, identicalor different, denote a C₁₋₂ alkyl residue,

[0013] X and Y or Y and Z together denote a bond, preferably X and Ytogether denote a bond,

[0014] A denotes an optionally at least mono-substituted aryl orheteroaryl residue, preferably an optionally at least mono-substitutedaryl residue, particularly preferably an optionally at leastmono-substituted phenyl residue, in the form of the racemates,diastereomers or enantiomers thereof as a free base or a correspondingphysiologically acceptable salt.

[0015] The term “alkyl residue” includes for the purposes of the presentinvention linear or branched hydrocarbon residues. The alkyl residuesare preferably selected from the group consisting of methyl, ethyl,propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, neopentyland n-hexyl.

[0016] The term “aryl residue” includes for the purposes of the presentinvention aromatic hydrocarbons. If the aryl residue comprises more thanone substituent, these may be identical or different. The aryl residueis preferably a phenyl residue optionally at least mono-substituted withF, Cl, Br, CHF₂, CF₃, OH, OCF₃, OR, NR⁷R⁸, SR⁶, phenyl, SO₂—CH₃,SO₂—CF₃, C₁₋₆ alkyl, CN, COOR⁶, CONR⁷R⁸, in which

[0017] R⁶ denotes a C₁₋₆ alkyl, a phenyl, a benzyl or a phenethylresidue,

[0018] R⁷ and R⁸, identical or different, denote H, a C₁₋₆ alkyl, aphenyl, a benzyl or a phenethyl residue.

[0019] Two substituents of the aryl residue may also form a saturated orunsaturated hydrocarbon ring optionally comprising heteroatoms on thearyl residue, preferably an —OCH₂O—, —OCH₂CH₂O—, —CH═CHO—, —CH═C(CH₃)O—or —(CH₂)₄ ring. Likewise preferred is a substituted phenyl residue,whose two substituents form an —OCH₂O—, —OCH₂CH₂O—, —CH═CHO—,—CH═C(CH₃)O— or —(CH₂)₄ ring.

[0020] The term “cycloalkyl residue” includes for the purposes of thepresent invention saturated cyclic hydrocarbon residues or alkylresidues, which comprise such a sub-structure. Preferably the cycloalkylresidues are selected from the group consisting of cyclopropyl,cyclopropylmethyl, methylcyclopropyl, cyclobutyl, 1-cyclopropylethyl,2-cyclopropylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl andcycloheptyl.

[0021] The term “heteroaryl residue” denotes for the purposes of thepresent invention a preferably 5- or 6-membered cyclic aromatic residue,which comprises one or more heteroatoms if the heteroaryl residuecomprises more than one heteroatom, these may be identical or different.The heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur are preferred.

[0022] If the heteroaryl residue comprises more than one substituent,these may be identical or different.

[0023] The heteroaryl residue is preferably an optionally at leastmono-substituted furanyl, thiophenyl, pyrrolyl, pyridine, pyrimidinyl,quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl residue.

[0024] The heteroaryl residue may preferably be mono- or polysubstitutedwith a substituent selected from the group consisting of F, Cl, Br,CHF₂, CF₃, OH, OCF₃, OR⁶, NR⁷R⁸, SR⁶, phenyl, SO₂—CH₃, SO₂—CF3, C₁₋₆alkyl, CN, COOR⁶ and CONR⁷R⁸, in which the residues R⁶, R⁷ and R⁸ havethe above-stated meaning.

[0025] Two substituents of the heteroaryl residue may also form asaturated or unsaturated hydrocarbon ring optionally comprisingheteroatoms on the heteroaryl residue, preferably an —OCH₂O—,—OCH₂CH₂O—, —CH═CHO—, —CH═C(CH₃)O— or —(CH₂)₄ring.

[0026] The following substituted 1-aryl-but-3-enylamine and1-aryl-but-2-enylamine compounds and the corresponding physiologicallyacceptable salts thereof, preferably the hydrochlorides thereof, arevery particularly preferred:

[0027] Dimethyl-[phenyl-(2-phenyl-cyclohex-1-enyl)-methyl]-amine,

[0028]{[2-(4-Chloro-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0029] [(2-Benzyl-cyclohex-1-enyl)-phenyl-methyl]-dimethyl-amine,

[0030]{[2-(4-Fluoro-3-methyl-phenyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,

[0031] Dimethyl-[phenyl-(2-o-tolyl-cyclohex-1-enyl)-methyl]-amine,

[0032] [(2-Cyclopentyl-cyclohex-1-enyl)-phenyl-methyl]-dimethyl-amine,

[0033] Dimethyl-[phenyl- (2-m-tolyl-cyclohex-1-enyl)-methyl]-amine,

[0034] (Bicyclohexyl-1-en-2-yl-phenyl-methyl)-dimethyl-amine,

[0035]{[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0036] Dimethyl-[(2-phenethyl-cyclohex-1-enyl)-phenyl-methyl]-amine,

[0037]{[2-(3-Methoxy-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0038]Dimethyl-{phenyl-[2-(3-phenyl-propyl)-cyclohex-1-enyl]-methyl}-amine,

[0039]{[2-(2-Chloro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0040]{[2-(4-Fluoro-benzyl)-cyclohex-1-enyl-phenyl-methyl}-dimethyl-amine,

[0041]{[2-(3-Methoxy-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0042]{[2-(3-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0043]{[2-(2-Methoxy-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0044] {[2-(3,5-Difluoro-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0045]{[2-(2-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,

[0046]{[2-(2-Chloro-benzyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,

[0047]{[2-(3-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,

[0048]Dimethyl-{phenyl-[2-(3-trifluoromethyl-benzyl)-cyclohex-1-enyl]-methyl}-amine,

[0049] Dimethyl-[(2-phenethyl-cyclohex-1-enyl)-phenyl-methyl]-amine,

[0050] 3-[6-(Dimethylamino-phenyl-methyl)-cyclohex-1-enyl]-phenol,

[0051]Dimethyl-{phenyl-(2-(4-trifluoromethylphenyl)-cyclohex-1-enyl]-methyl}-amine,

[0052]2-Chloro-5-[6-(dimethylamino-phenyl-methyl)-cyclohex-1-enyl]-phenol,

[0053]{[2-(4-Methoxy-phenyl)-cyclohex-2-enyl]-phenyl-methyl}-dimethyl-amine,

[0054]{[2-(4-Chloro-phenyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine and

[0055]Dimethyl-[(2-phenyl-cyclohex-1-enyl)-(4-trifluoromethyl-phenyl)-methyl]-amine.

[0056] The substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylaminecompounds of the general formula I according to the invention or thecorresponding physiologically acceptable salts thereof may in each casebe present in the form of the racemates thereof, the pure enantiomersthereof, the pure diastereomers thereof, or in the form of a mixture ofat least two of the above-stated stereoisomers. The substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds of thegeneral formula I according to the invention may likewise also in eachcase be present in the form of mixtures of the enantiomers ordiastereomers thereof, in particular in the form of thecis/trans-diastereomers thereof. These mixtures may comprise therespective stereoisomers in any desired mixing ratio.

[0057] The present invention relates further to a process for theproduction of substituted 1-aryl-but-3-enylamine and1-aryl-but-2-enylamine compounds of the above-stated general formula I,according to which at least one Mannich base of the general formula II,

[0058] in which R¹, R², R⁴, R⁵ and A have the above-stated meaning, isreacted with at least one organometallic compound of the general formulaR³—B, in which B denotes MgCl, MgBr, MgI or Li and R³ has theabove-stated meaning, to yield an alcohol of the general formula III,

[0059] in which the residues R¹ to R² and A have the above-statedmeaning, and this is optionally purified by conventional methods and/oroptionally isolated by conventional methods, and reacted with a suitableacid optionally in the presence of a suitable solvent to yield at leastone compound of the above-stated general formula I.

[0060] The process for the production of alcohols of the general formulaIII is for example also described in DE 199 15 601 A1. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

[0061] In a preferred embodiment of the process according to theinvention, a protonic acid, a Lewis acid or a mixture thereof is used assuitable acid for reacting the alcohol of the general formula III toyield the compound of the general formula I.

[0062] Hydrogen bromide, hydrogen chloride, formic acid, are preferablyused as the protonic acid, and trimethylsilyl iodide orchlorotrimethylsilane are preferably used as the Lewis acid.

[0063] Water may be used as suitable solvent during reaction of thealcohol of the general formula III to yield the compound of the generalformula I. Moreover, organic solvents, such as for example acetonitrile,optionally also in a mixture with water, may also be used.

[0064] The temperature may vary over a wide range during reaction of thealcohol of the general formula III with the acid. The reaction ispreferably performed at a temperature of 5 to 150° C., particularlypreferably at a temperature of 10 to 130° C., very particularlypreferably at a temperature of 15 to 120° C.

[0065] The process according to the invention may also be performedsemi- or fully automatically as parallel synthesis of a group of1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds of thegeneral formula I.

[0066] The substituted 1-aryl-but-3-enylamine and.1-aryl-but-2-enylamine compounds of the general formula I according tothe invention may be isolated by the process according to the inventionboth in the form of their free base and in the form of a salt.

[0067] Both conversion of the free base of the compounds according tothe invention of the general formula I into a correspondingphysiologically acceptable salt and release of the free base from thecorresponding physiologically acceptable salt may proceed in accordancewith conventional methods known to the person skilled in the art.

[0068] Conversion of the free base of a compound according to theinvention of the general formula I into its correspondingphysiologically acceptable salt may proceed for example withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, lactic acid, citric acid, glutamic acid or asparticacid. The free base of the respective compound of the general formula Iaccording to the invention may also be converted with the free acid or asalt of a sugar substitute, such as for example saccharin, cyclamate oracesulfame, into the corresponding physiologically acceptable salt.

[0069] Conversion of the free base of a compound of the general formulaI according to the invention into its corresponding hydrochloride maypreferably also be obtained by combining the compound of the generalformula I according to the invention, dissolved in a suitable organicsolvent, such as for example butan-2-one (methyl ethyl ketone), as afree base with trimethylsilyl chloride (TMSCl).

[0070] If it is desired to separate the substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds of thegeneral formula I according to the invention into their variousenantiomers and/or diastereomers, this may proceed in accordance withconventional processes known to the person skilled in the art. Examplesare chromatographic separation processes, in particular liquidchromatography processes at standard pressure or at elevated pressure,preferably MPLC and HPLC methods, and fractional crystallisationprocesses. Individual enantiomers, e.g. diastereomeric salts formed bymeans of HPLC on a chiral phase or by means of crystallisation withchiral acids, such as (+)-tartaric acid, (−)-tartaric acid or(+)-10-camphorsulfonic acid, may here in particular be separated fromone another.

[0071] The substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylaminecompounds of the general formula I according to the invention aretoxicologically safe and are therefore suitable as pharmaceutical activeingredients in pharmaceutical preparations.

[0072] The present invention therefore also provides pharmaceuticalpreparations which contain at least one substituted1-aryl-but-3-enylamine or 1-aryl-but-2-enylamine compound of the generalformula I according to the invention and optionally physiologicallyacceptable auxiliary substances.

[0073] The pharmaceutical preparations according to the invention aresuitable for combatting pain or for the treatment of depression,hypotension, hypertension, senile dementia, Alzheimer's disease, generalcognitive dysfunction, tinnitus, hardness of hearing, epilepsy, obesity,cachexia, urinary incontinence, for anxiolysis or for diuresis.

[0074] The use of at least one substituted 1-aryl-but-3-enylamine or1-aryl-but-2-enylamine compound of the general formula I for theproduction of a pharmaceutical preparation for combatting pain, for thetreatment of depression, hypotension, hypertension, senile dementia,Alzheimer's disease, general cognitive dysfunction, tinnitus, hardnessof hearing, epilepsy, obesity, cachexia, urinary incontinence, foranxiolysis or for diuresis is likewise the subject matter of the presentinvention.

[0075] The pharmaceutical preparation according to the invention may bepresent as liquid, semisolid or solid dosage forms, for example in theform of solutions for injection, drops, succi, syrups, sprays,suspensions, tablets, patches, capsules, transdermal delivery systems,suppositories, ointments, creams, lotions; gels, emulsions, aerosols orin multiparticulate form, for example in the form of pellets orgranules, and also administered as such.

[0076] In addition to at least one substituted 1-aryl-but-3-enylamine or1-aryl-but-2-enylamine compound of the general formula I according tothe invention, the pharmaceutical preparations according to theinvention conventionally contain further physiologically acceptablepharmaceutical auxiliary substances, which are preferably selected fromthe group consisting of matrix materials, fillers, solvents, diluents,surface-active substances, dyes, preservatives, suspending agents, slipagents, lubricants, aromas and binders.

[0077] Selection of the auxiliary substances and the quantities thereofwhich are to be used depends upon whether the pharmaceutical preparationis to be administered orally, subcutaneously, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally, rectally or topically, for example ontoinfections of the skin, mucous membranes or eyes. Preparations in theform of tablets, coated tablets, capsules, granules, pellets, drops,succi and syrups are preferred for oral administration, while solutions,suspensions, readily reconstitutible dried preparations and sprays arepreferred for parenteral, topical and inhalatory administration.Compounds according to the invention of the general formula I in a depotin dissolved form or in a dressing, optionally with the addition of skinpenetration promoters, are suitable percutaneous administrationpreparations. Orally or percutaneously administrable preparations mayalso release the compounds of the general formula I according to theinvention in delayed manner.

[0078] Production of the pharmaceutical preparations according to theinvention may proceed with the assistance of conventional means,devices, methods and processes known to the person skilled in the art,such as are described for example in “Remington's PharmaceuticalSciences”, Ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton,Pa. (1985), in particular in part 8, chapters 76 to 93. Thecorresponding literature description is hereby introduced as a referenceand is deemed to be part of the disclosure.

[0079] The quantity of the respective substituted 1-aryl-but-3-enylamineor 1-aryl-but-2-enylamine compound of the general formula I according tothe invention to be administered to the patient may vary and is forexample dependent on the weight or age of the patient and on the mode ofadministration, the indication and the severity of the complaint.Conventionally, at least one substituted 1-aryl-but-3-enylamine-or1-aryl-but-2-enylamine compound of the general formula I according tothe invention is administered in a quantity of 0.005 to 500 mg/kg, inparticular of 0.05 to 5 mg/kg, of patient body weight.

[0080] Pharmacological Investigations:

[0081] Analgesic Testing by Writhing Test in Mice

[0082] The investigation into analgesic efficacy was performed byphenylquinone-induced writhing in mice (modified after: I. C. Hendershotand J. Forsaith (1959) J. Pharmacol. Exp. There. 125, 237-240). MaleNMRI mice weighing from 25-30 g were used for this purpose. 10 minutesafter intravenous administration of the test compounds, groups of 10animals per dose of a compound received 0.3 ml/mouse of a 0.02% aqueoussolution of phenylquinone (phenylbenzoquinone, sigma, Deisenhofen;production of the solution with addition of 5% ethanol and storage inwater bath at 45° C.), administered intraperitoneally. The animals wereplaced individually in observation cages. A push button counter was usedto record the number of pain-induced stretching movements (writhingreactions=straightening of the torso with stretching of the rearextremities) for 5-20 minutes after phenylquinone administration. Thecontrol was provided by animals who received only physiological commonsalt solution. All the compounds were tested at the standard dosage of10 mg/kg. The percentage inhibition (%inhibition) of the writhingreaction by a compound of the general formula I according to theinvention was calculated according to the following formula:${\% \quad {Inhibition}} = {100 - {\frac{{Writhing}\quad {reactions}\quad {of}\quad {treated}\quad {animals}}{{Writhing}\quad {reactions}\quad {of}\quad {control}\quad {animals}} \times 100}}$

[0083] The invention is explained below with reference to Examples.These explanations are given merely by way of example and do notrestrict the general concept of the invention.

EXAMPLES

[0084] The yields of the example compounds according to the inventionwere not optimised.

[0085] All temperatures are uncorrected.

[0086] Production of the alcohols used in each case in the Examplesgiven below proceeded in accordance with methods such as those describedin DE 199 15 601. The corresponding literature description is herebyintroduced as a reference and is deemed to be part of the disclosure.

[0087] General Procedure 1

[0088] In a synthesiser (Syro II, Multisyntech), 10 mg portions of therespective alcohol of the general formula III were combined with 2 ml offormic acid and heated for two hours to 90° C. After the reaction, thereaction mixture was evaporated in a vacuum centrifuge. The substanceswere analysed by means of ESI-MS. The alcohols used in each case and thecompounds of the general formula I obtained by way of example are listedin Table 1 below. TABLE 1 1-Aryl-but-3-enylamine or 1-aryl-but-2-Alcohol of the general enylamine compound of Example formula III usedthe general formula I 1 2-(Dimethylamino- Dimethyl-[phenyl-(2-phenyl-methyl)-1- phenyl-cyclohex-1-enyl)- phenyl-cyclohexanolmethyl]-amine 2 1-(4-Chloro-phenyl)-2- {[2-(4-Chloro-phenyl)-(dimethylamino-phenyl- cyclohex-1-enyl]-phenyl- methyl)-cyclohexanolmethyl}-dimethyl-amine 3 1-Benzyl-2- [(2-Benzyl-cyclohex-1-(dimethylamino-phenyl- enyl)-phenyl-methyl]- methyl)-cyclohexanoldimethyl-amine 4 2-(dimethylamino- {[2-(4-Fluoro-3-methyl-phenyl-methyl)-1-(4- phenyl)-cyclohex-1- fluoro-3-methylphenyl)-enyl]-phenyl-methyl}- cyclohexanol dimethyl-amine 5 2-(Dimethylamino-Dimethyl-[phenyl-(2-o- phenyl-methyl)-1-o- tolyl-cyclohex-1-enyl)-tolyl-cyclohexanol methyl]-amine 6 1-Cyclopentyl-2- [(2-Cyclopentyl-(dimethylamino-phenyl- cyclohex-1-enyl)-phenyl- methyl)-cyclohexanolmethyl]-dimethyl-amine 7 2-(Dimethylamino- Dimethyl-[phenyl-(2-m-phenyl-methyl)-1-m- tolyl-cyclohex-1-enyl)- tolyl-cyclohexanolmethyl]-amine 8 2-(Dimethylamino- (Bicyclohexyl-1-en-2-yl-phenyl-methyl)- phenyl-methyl)-dimethyl- bicyclohexyl-1-ol amine 92-(Dimethylamino- {[2-(4-Fluoro-phenyl)- phenyl-methyl)-1-(4-cyclohex-1-enyl]-phenyl- fluoro-phenyl)- methyl}-dimethyl-aminecyclohexanol 10 2-(Dimethylamino- Dimethyl-[(2-phenethyl-phenyl-methyl)-1- cyclohex-1-enyl)-phenyl- phenethyl-cyclohexanolmethyl]-amine 11 2-(Dimethylamino- {[2-(3-Methoxy-phenyl)-phenyl-methyl)-1-(3- cyclohex-1-enyl]-phenyl- methoxyphenyl)-methyl}-dimethyl-amine cyclohexanol 12 2-(Dimethylamino-Dimethyl-{phenyl-[2-(3- phenyl-methyl-)-1-(3- phenyl-propyl)-cyclohex-phenyl-propyl)- 1-enyl]-methyl}-amine cyclohexanol 131-(2-Chloro-benzyl)-2- {[2-(2-Chloro-benzyl)- dimethylamine-phenyl-cyclohex-1-enyl]-phenyl- methyl)-cyclohexanol methyl}-dimethyl-amine 142-(Dimethylamino- {[2-(4-Fluoro-benzyl)- phenyl-methyl)-1-(4-cyclohex-1-enyl]-phenyl- fluoro-benzyl)- methyl}-dimethyl-aminecyclohexanol 15 2-(Dimethylamino- {[2-(3-Methoxy-benzyl)-phenyl-methyl)-1-(3- cyclohex-1-enyl]-phenyl- methoxy-benzyl)-methyl}-dimethyl-amine cyclohexanol 16 2-(Dimethylamino-{[2-(3-Fluoro-benzyl)- phenyl-methyl)-1-(3- cyclohex-1-enyl]-phenyl-fluoro-benzyl)- methyl}-dimethyl-amine cyclohexanol 17 2-(Dimethylamino-{[2-(2-Methoxy-benzyl)- phenyl-methyl)-1-(2- cyclohex-1-enyl]-phenyl-methoxy-benzyl)- methyl}-dimethyl-amine cyclohexanol 18 1-(3,5-Difluoro-{[2-(3,5-Difluoro- benzyl)-2- benzyl)-cyclohex-1- (dimethylamino-phenyl-enyl]-phenyl-methyl}- methyl)-cyclohexanol dimethyl-amine

[0089] General Procedure 2

[0090] The alcohol of the general formula III used in each case wasrefluxed with aqueous HBr, (47 wt. %; approx. 10 ml per mmol of alcohol)for five hours. The mixture was then made basic with sodium hydroxidesolution (32 wt. %) and extracted three times with dichloromethane(approx. 10 ml per mmol of alcohol). The combined extracts were driedover sodium sulfate, filtered and evaporated.

[0091] The crude products obtained in this way were converted into thecorresponding hydrochlorides without further purification. To this end,the respective crude product was dissolved in approx. 10 ml of2-butanone per gram of free base, half a mol equivalent of water wasthen added, followed by 1.1 mol equivalents of chlorotrimethylsilane,and the mixture was stirred overnight. Then already precipitatedhydrochlorides were filtered out or the hydrochlorides were precipitatedby the addition of diethyl ether and/or n-hexane and then vacuum-dried.

[0092] The alcohols used in each case, the hydrochlorides obtained ofthe exemplary compounds of the general formula I, their yields andoptionally the solvent used for precipitation of the hydrochloride arelisted Table 2 below. TABLE 2 1-Aryl-but-3-enylamine or 1-aryl-but-2-Yield of enylamine compound of hydrochloride Precipitation ExampleAlcohol used the general formula I in g with 19 2-(Dimethylamino-{[2-(2-Fluoro-benzyl)- 1.31 phenyl-methyl)-1- cyclohex-1-enyl)-(2-fluoro-benzyl)- phenyl-methyl}- cyclohexanol dimethyl-aminehydrochloride 20 1-(2-Chloro- {[2-(2-Chloro-benzyl)- 2.17 Diethylbenzyl)-2- cyclohex-1-enyl]- ether (dimethylamine- phenyl-methyl}-phenyl-methyl)- dimethyl-amine cyclohexanol hydrochloride 212-(Dimethylamino- {[2-(3-Fluoro-benzyl)- 0.89 phenyl-methyl)-1-cyclohex-1-enyl)- (3-fluoro-benzyl)- phenyl-methyl}- cyclohexanoldimethyl-amine hydrochloride 22 2-(Dimethylamino- Dimethyl-{phenyl-[2-2.64 phenyl-methyl)-1- (3-trifluoromethyl- (3- benzyl)-cyclohex-1-trifluoromethyl- enyl]-methyl}-amine benzyl)- hydrochloride cyclohexanol23 2-(Dimethylamino- Dimethyl-[(2- 1.45 phenyl-methyl)-1-phenethyl-cyclohex-1- phenethyl- enyl)-phenyl-methyl]- cyclohexanolamine hydrochloride 25 2-(Dimethylamino- Dimethyl-{phenyl-(2- 0.75Diethyl phenyl-methyl)-1- (4- ether (4- trifluoromethylphenyl)trifluoromethyl- -cyclohex-1-enyl]- phenyl)- methyl}-amine cyclohexanol26 2-Chloro-5-[2- 2-Chloro-5-[6- 0.63 (dimethylamino-(dimethylamino-phenyl- phenyl-methyl)-1- methyl)-cyclohex-1- hydroxy-enyl]-phenol cyclohexyl]-phenol 28 1-(4-Chloro- {[2-(4-Chloro-phenyl)-1.28 Diethyl phenyl)-2- cyclohex-1-enyl]- ether (dimethylamino-phenyl-methyl}- phenyl-methyl)- dimethyl-amine cyclohexanolhydrochloride 29 2-[Dimethylamino- Dimethyl-[(2-phenyl- 1.11 n-Hexane(4- cyclohex-1-enyl)-(4- trifluoromethyl- trifluoromethyl-phenyl)-methyl]-1- phenyl)-methyl]-amine phenyl- hydrochloridecyclohexanol

Example 24

[0093] Elimination with trimethylsilyl iodide

[0094] The alcohol3-[2-dimethylamino-phenyl-methyl)-1-hydroxy-cyclohexyl]-phenol wasdissolved or suspended in a saturated solution of sodium iodide inacetonitrile (approx. 3 ml per mmol of alcohol), three mol equivalentsof trimethylchlorosilane were added dropwise and the mixture was stirredovernight.

[0095] For working up, the mixture was adjusted to pH 8 with saturatedsodium hydrogencarbonate solution and then sodium thiosulfate solutionwas added (approx. 0.1 M) until a largely clear and colourless solutionwas obtained. Extraction was performed three times with diethyl ether(approx. 10 ml per mmol of alcohol), the combined extracts were driedover sodium sulfate, filtered and evaporated. The crude product thusobtained was converted into the hydrochloride without furtherpurification. To this end, the crude product was dissolved in approx. 10ml of acetone per gram of base, 1.1 mol equivalents of hydrochloric acid(32 wt. %) were added and the mixture was stirred overnight. Then theprecipitated 3-[6-(dimethylamino-phenyl-methyl)-cyclohex-1-enyl]-phenolhydrochloride was filtered out and vacuum-dried.

Example 27

[0096] The alcohol2-(dimethylamino-phenyl)-1-(4-methoxy-phenyl)-cyclohexanol was dissolvedin approx. 10 ml of 2-butanone per gram of alcohol, a half molequivalent of water was added, followed by 1.1 mol equivalents ofchlorotrimethylsilane, and the mixture was stirred overnight. Theprecipitated{[2-(4-methoxy-phenyl)-cyclohex-2-enyl]-phenyl-methyl)-dimethylaminehydrochloride was filtered out, the corresponding base was released andpurified chromatographically (silica gel, hexane/ethyl acetate 3:2).Then the purified{[2-(4-methoxy-phenyl)-cyclohex-2-enyl]-phenyl-methyl)-dimethylamine wasprecipitated as the hydrochloride as described above.

[0097] Pharmacological Investigations:

[0098] The in-depth investigation of the compounds of the generalformula I according to the invention for analgesic efficacy wasperformed by phenylquinone-induced writhing in mice, as described above.

[0099] The investigated compounds according to the invention exhibitedan analgesic action.

[0100] The results of selected writhing investigations are summarised inTable 3 below. TABLE 3 Analgesic testing by writhing test on the mouse1-Aryl-but-3-enylamine or 1- % Inhibition of aryl-but-2-enylaminecompound writhing Example of the general formula I reaction* 19{[2-(2-Fluoro-benzyl)- 87% (10 mg/kg) cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine 20 {[2-(2-Chloro-benzyl)- 63% (10 mg/kg)cyclohex-1-enyl]-phenyl- methyl}-dimethyl-amine 21{[2-(3-Fluoro-benzyl)- 67% (10 mg/kg) cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine 22 Dimethyl-{phenyl-[2-(3- 46% (21.5 mg/kg)trifluoromethyl-benzyl)- cyclohex-1-enyl]-methyl}- amine 23Dimethyl-[(2-phenethyl- 67% (10 mg/kg) cyclohex-1-enyl)-phenyl-methyl]-amine 24 3-[6-(Dimethylamino-phenyl- 76% (10 mg/kg)methyl)-cyclohex-1-enyl]- phenol hydrochloride 27{[2-(4-Methoxy-phenyl)- 47% (10 mg/kg) cyclohex-2-enyl]-phenyl-methyl}-dimethyl-amine hydrochloride 28 {[2-(4-Chloro-phenyl)- 71% (10mg/kg) cyclohex-1-enyl]-phenyl- methyl}-dimethyl-amine hydrochloride 29Dimethyl-[(2-phenyl-cyclohex- 40% (10 mg/kg) 1-enyl)-(4-trifluoromethyl-phenyl)-methyl]-amine hydrochloride

1. Substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylaminecompounds of the general formula I,

in which R¹ and R², identical or different, denote a C₁₋₆ alkyl residueor together form a (CH₂)₂₋₆ ring, which may also be substituted orbenzo-fused with at least one optionally at least mono-substituted arylor heteroaryl residue, R³ denotes a C₃₋₆ alkyl, a C₃₋₇ cycloalkyl, anoptionally at least mono-substituted aryl or heteroaryl residue or anoptionally at least mono-substituted aryl or heteroaryl residue attachedvia a C₁₋₃ alkylene group, R⁴ and R⁵, identical or different, denote aC₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a phenyl, a benzyl or a phenethyl or R⁴and R⁵ together form a (CH₂)₃₋₆ or —CH₂—CH₂—O—CH₂—CH₂ ring, X and Y or Yand Z together denote a bond, A denotes an optionally at leastmono-substituted aryl or heteroaryl residue, in the form of theracemates, diastereomers or enantiomers thereof as a free base or acorresponding physiologically acceptable salt.
 2. Substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds according toclaim 1, characterised in that R¹ and R² together form a (CH₂)₂₋₆ ring,which may also be substituted or benzo-fused with at least oneoptionally at least mono-substituted aryl or heteroaryl residue. 3.Substituted 1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compoundsaccording to claim 1 or 2, characterised in that R¹ and R² together forma cyclohexyl ring, which may also be substituted with an optionally atleast mono-substituted phenyl residue.
 4. Substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds according toone of claims 1 to 3, characterised in that R³denotes an optionally atleast mono-substituted aryl residue or an optionally at leastmono-substituted aryl residue attached via a C₁₋₃ alkylene group,preferably an optionally at least mono-substituted phenyl, benzyl orphenethyl residue.
 5. Substituted 1-aryl-but-3-enylamine and1-aryl-but-2-enylamine compounds according to one of claims 1 to 4,characterised in that the residues R⁴ and R⁵, identical or different,denote a C₁₋₆ alkyl residue or together form a —(CH₂)₅— or—CH₂—CH₂—O—CH₂—CH₂ ring, preferably, identical or different, denote aC₁₋₂ alkyl residue.
 6. Substituted 1-aryl-but-3-enylamine and1-aryl-but-2-enylamine compounds according to one of claims 1 to 5,characterised in that X and Y together denote a bond.
 7. Substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds according toone of claims 1 to 6, characterised in that A denotes an optionally atleast mono-substituted aryl residue, preferably an optionally at leastmono-substituted phenyl residue.
 8. Substituted 1-aryl-but-3-enylamineand 1-aryl-but-2-enylamine compounds according to one or more of claims1 to 7: Dimethyl-[phenyl-(2-phenyl-cyclohex-1-enyl)-methyl]-amine,{[2-(4-Chloro-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,[(2-Benzyl-cyclohex-1-enyl)-phenyl-methyl]-dimethyl-amine,{[2-(4-Fluoro-3-methyl-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,Dimethyl-[phenyl-(2-o-tolyl-cyclohex-1-enyl)-methyl]-amine,[(2-Cyclopentyl-cyclohex-1-enyl)-phenyl-methyl]-dimethyl-amine,Dimethyl-[phenyl-(2-m-tolyl-cyclohex-1-enyl)-methyl]-amine,(Bicyclohexyl-1-en-2-yl-phenyl-methyl)-dimethyl-amine,{[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,Dimethyl-[(2-phenethyl-cyclohex-1-enyl)-phenyl-methyl]-amine,{[2-(3-Methoxy-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,Dimethyl-{phenyl-[2-(3-phenyl-propyl)-cyclohex-1-enyl]-methyl}-amine,{[2-(2-Chloro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(4-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(3-Methoxy-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(3-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,{[2-(2-Methoxy-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(3,5-Difluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(2-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,{[2-(2-Chloro-benzyl)-cyclohex-1-enyl]-phenyl-methyl)-dimethyl-amine,{[2-(3-Fluoro-benzyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,Dimethyl-{phenyl-[2-(3-trifluoromethyl-benzyl)-cyclohex-1-enyl]-methyl}-amine,Dimethyl-[(2-phenethyl-cyclohex-1-enyl)-phenyl-methyl)-amine,3-[6-(Dimethylamino-phenyl-methyl)-cyclohex-1-enyl]-phenol,Dimethyl-{phenyl-(2-(4-trifluoromethylphenyl)-cyclohex-1-enyl]-methyl}-amine,2-Chloro-5-[6-(dimethylamino-phenyl-methyl)-cyclohex-1-enyl]-phenol,{[2-(4-Methoxy-phenyl)-cyclohex-2-enyl]-phenyl-methyl}-dimethyl-amine,{[2-(4-Chloro-phenyl)-cyclohex-1-enyl]-phenyl-methyl}-dimethyl-amine,Dimethyl-[(2-phenyl-cyclohex-1-enyl)-(4-trifluoromethyl-phenyl)-methyl]-amine,and the corresponding physiologically acceptable salts, preferably thehydrochlorides thereof.
 9. A process for the production of substituted1-aryl-but-3-enylamine and 1-aryl-but-2-enylamine compounds of thegeneral formula I according to one or more of claims 1 to 8,characterised in that at least one Mannich base of the general formulaII,

in which R¹, R², R⁴, R⁵ and A have the meaning according to the generalformula I according to claim 1, is reacted with at least oneorganometallic compound of the general formula R³—B, in which B denotesMgCl, MgBr, MgI or Li and R³ has the meaning according to the generalformula I according to claim 1, to yield at least one alcohol of thegeneral formula III,

in which the residues R¹ to R⁵ and A have the meaning according to thegeneral formula I according to claim 1, and this is optionally purifiedby conventional methods and/or optionally isolated by conventionalmethods, and reacted with a suitable acid optionally in the presence ofa suitable solvent to yield at least one compound of the general formulaI according to claim
 1. 10. A process according to claim 9,characterised in that a protonic acid, a Lewis acid or a mixture thereofis used as suitable acid.
 11. A process according to claim 10,characterised in that hydrogen bromide, hydrogen chloride or formic acidis used as protonic acid.
 12. A process according to claim 10 or 11,characterised in that trimethylsilyl iodide or chlorotrimethylsilane isused as the Lewis acid.
 13. A process according to one of claims 9 to12, characterised in that reaction of the alcohol with the acid isperformed at a temperature of 5 to 150° C., preferably at a temperatureof 10 to 130° C., particularly preferably at a temperature of 15 bis120° C.
 14. A pharmaceutical preparation containing at least onesubstituted 1-aryl-but-3-enylamine or 1-aryl-but-2-enylamine compoundaccording to one of claims 1 to 8 and optionally physiologicallyacceptable auxiliary substances.
 15. A pharmaceutical preparationaccording to claim 14 for combatting pain.
 16. A pharmaceuticalpreparation according to claim 14 for the treatment of depression.
 17. Apharmaceutical preparation according to claim 14 for the treatment ofhypotension.
 18. A pharmaceutical preparation according to claim 14 forthe treatment of hypertension.
 19. A pharmaceutical preparationaccording to claim 14 for the treatment of senile dementia.
 20. Apharmaceutical preparation according to claim 14 for the treatment ofAlzheimer's disease.
 21. A pharmaceutical preparation according to claim14 for the treatment of general cognitive dysfunction.
 22. Apharmaceutical preparation according to claim 14 for the treatment oftinnitus.
 23. A pharmaceutical preparation according to claim 14 for thetreatment of hardness of hearing.
 24. A pharmaceutical preparationaccording to claim 14 for the treatment of epilepsy.
 25. Apharmaceutical preparation according to claim 14 for the treatment ofobesity.
 26. A pharmaceutical preparation according to claim 14 for thetreatment of cachexia.
 27. A pharmaceutical preparation according toclaim 14 for the treatment of urinary incontinence.
 28. A pharmaceuticalpreparation according to claim 14 for anxiolysis.
 29. A pharmaceuticalpreparation according to claim 14 for diuresis.
 30. Use of at least onesubstituted 1-aryl-but-3-enylamine or 1-aryl-but-2-enylamine compoundaccording to one of claims 1 to 8 for the production of a pharmaceuticalpreparation for combatting pain, for the treatment of depression,hypotension, hypertension, senile dementia, Alzheimer's disease, generalcognitive dysfunction, tinnitus, hardness of hearing, epilepsy, obesity,cachexia or urinary incontinence or for anxiolysis or diuresis.